1. Technical Field
This invention relates to a hemolysis depressant and a plasticizer. More particularly, this invention relates to a hemolysis depressant exhibiting extremely high safety and permitting highly effective control of the phenomenon of hemolysis which possibly occurs in blood while in storage and to a resin composition for medical appliances, medical implements and blood preserving liquids which make use of the hemolysis depressant, to a plasticizer exhibiting no toxicity and possessing highly desirable compatibility with vinyl chloride type resins and to vinyl chloride type resin composition for medical appliances and medical implements which make use of the plasticizer.
2. Background Art
When blood flows out of the blood vessel, it begins to show a visible sign of coagulation within 10 to 20 minutes exposure to ambient conditions. The clot which formed by the coagulation is the final product of a series of chemical reactions which proceed during the conversion of fibrinogen into fibrin. The fibrin are interconnected and, during the course of the interconnection, erythrocytes are entrapped in the clot. In order for the blood for transfusion to retain its original liquid state, therefore, a measure to preclude the normal reactions responsible for the hemal coagulation must be taken during the extraction of the blood from a donor. Heretofore, the practice of adding a liquid anticoagulant as a blood preserving liquid to the freshly extracted blood has been in vogue. The liquid anticoagulant which is in popular use nowadays is intended to effect the preclusion of the hemal coagulation by chelating the calcium ion which constitutes an important factor during the course of coagulation.
Incidentally, the blood for transfusion secured as described above is treated, when necessary, for separation of some of the components thereof and then is placed as in a blood bag, for example, to be preserved until use. When whole blood or a blood component such as concentrated red cells (CRC) is preserved for a long time, there ensues the so-called hemolysis, i.e. a phenomenon which involves external liberation of hemoglobin from the erythrocyte. As main causes for the hemolysis, there can be cited the change in the pressure of osmosis due to a difference in the ion composition in the blood, the difference in the pressure of colloidal osmosis due to such proteinaceous components as hemoglobin, the change in membrane proteins and lipids of erythrocytes, the hindrance to the active transport of Na.sup.+ and K.sup.+ and the actions of medicines and poisons. The most important factor consists in the liquid anticoagulant to be used. Thus, numerous efforts have been devoted to improve the liquid anticoagulants. All the liquid anticoagulants currently in use are claimed to produce an anticoagulant action and an action for protection of erythrocytes as well. In the liquid anticoagulants of this type, however, the function as a protector for erythrocytes has not yet reached a point where it deserves to be called sufficient.
It is likewise important that the container such as the blood bag for preserving the collected blood should be inactive to blood components. In the blood containers and other similar medical implements which are currently in use, those made of flexible vinyl chloride resin are predominant. The di-2-ethylhexyl phthalate (DOP) which is contained as a plasticizer in the flexible vinyl chloride resin for such medical implements possesses a large capacity for migration. It is known that when the flexible vinyl chloride resin is exposed to blood, the di-2-ethylhexyl phthalate exudes from the container wall and dissolves into the blood (The Japanese Journal of Medical Instrumentation, 54, 221 (1984)). It has been reported that this di-2-ethylhexyl phthalate hinders the aggregating ability of platelets (Journal of Japan Society of Blood Transfusion, 28(3) 282 (1981)). When the preserving container made of such flexible vinyl chloride resin as described above is used to preserve blood, for example, there is the possibility that the di-2-ethylhexyl phthalate will enter the donee's blood vessel as entrained by the preserved blood during the course of transfusion. This possibility poses a problem from the standpoint of the adverse effect exerted by this compound upon the function of platelets.
For the solution of this problem, the feasibility of the use of a material not containing this di-2-ethylhexyl phthalate has been studied. It has been learnt that when blood is preserved in containers made of materials not containing di-2-ethylhexyl phthalate, the erythrocytes in the preserved blood are hemolyzed during the course of preservation. A search of the cause for this hemolysis has revealed that di-2-ethylhexyl phthalate is effective in hindering hemolysis (Blood, 646 1270-(1984)). In other words, when blood is preserved in a blood container made of the conventional flexible vinyl chloride resin which incorporates therein di-ethylhexyl phthalate as a plasticizer, the di-2-ethylhexyl phthalate dissolving into the preserved blood serves to hinder the hemolysis of erythrocytes.
As a measure against such an adverse phenomenon as described above, a contradictory method which comprises preserving blood in a container made of a material incapable of exuding an incorporated plasticizer (or a material not containing any plasticizer) and, prior to actual use of the preserved blood, adding di-2-ethylhexyl phthalate to the blood thereby preventing the blood from hemolysis has been proposed (U.S. Pat. No. 4,326,025). The idea of using di-2-ethylhexyl phthalate as a hemolysis depressant, however, is not desirable from the standpoint of physiological safety.
Further, the blood bag containing the blood extracted from a donor is generally forwarded to a hospital, as accompanied by a blood collection tube containing the same blood as that in the blood bag so that the blood in the tube may be used as a sample for testing the blood for adaptability to the patient's blood in advance of the transfusion. As the time of storage of this blood bag increases to approach the 21st day of extraction fixed officially (in Japan) for the availability of concentrated red cells, the blood contained in the blood collection tube yields to hemolysis in much the same way as described above. The hemoglobin liberated in consequence of the hemolysis brings about adverse effects on the results of various measurements performed for clinical test and interferes with the test. This fact has been posed as a problem.
As clearly gathered from the observations illustrated above, the desirability of developing a material capable of producing a notable protective action for erythrocytes has found enthusiastic recognition in various fields including the medical field.
At present, flexible vinyl chloride resins are widely used not only in medical appliances but also in food containers on account of their desirability in terms of moldability, flexibility, transparency, resistance to heat, and cost. For their feasibility in such food containers, the question of toxicity matters much. For this reason, the soft vinyl chloride resins used in the food containers generally incorporate therein as a plasticizer di-2-ethylhexyl phthalate which is accepted as a relatively safe compound in all the known plasticizers. Incidentally, di-2-ethylhexyl phthalate has been demostrated to possess a high migrating property and mono-2-ethylhexyl phthalate (MEHP), a metabolite of di-2-ethylhexyl phthalate, to possess mutagenicy [Yagi et al., Teratology, 14, 259 (1976)]. In view of the defective properties exhibited as described above by the conventional plasticizers coupled with the poor abilities manifested thereby in the control of the phenomenon of coagulation of blood platelets, the desirability of perfecting a safe substance capable of taking the place of di-2-ethylhexyl phthalate as a plasticizer has been finding enthusiastic recognition.
An object of this invention, therefore, is to provide a novel hemolysis depressant and plasticizer. Another object of this invention is to provide a resin composition for medical appliances, medical implements, and blood preserving liquids which make use of the novel hemolysis depressant. A further object of this invention is to provide vinyl chloride type resin compositions for medical appliances and medical implements which make use of the novel plasticizer.
This invention also aims to provide a hemolysis depressant capable of providing highly effective control of the phenomenon of hemolysis which occurs in blood during the course of preservation. Further, this invention aims to provide a hemolysis depressant which excels also in physiological safety. This invention also aims to provide a hemolysis depressant which can be incorporated in a resin composition or directly added to a liquid containing erythrocytes.
Further, this invention aims to provide a medical resin composition capable of very effectively controlling the phenomenon of hemolysis in a erythrocyte-containing liquid held in contact with the resin composition. This invention also aims to provide a flexible type medical resin composition which contains no plasticizer or contains substantially nonextractable plasticizer, excels in physiological safety and produces a highly desirable effects in the inhibition of hemolysis, and suits best as a material for medical implements such as the blood bag. This invention further aims to provide a rigid type medical resin composition which produces a highly desirable effect in the inhibition of hemolysis and suits most as a material for such medical implements as the blood collection tube.
In addition, this invention aims to provide a medical implement capable of preserving blood components represented by the erythrocyte in a erythrocyte-containing liquid intact for a long time. This invention further aims to provide a medical implement abounding with physiological safety.
This invention further aims to provide a blood preserving liquid which possesses a highly desirable ability to preserve erythrocytes and abounds with safety. This invention also aims to provide a blood preserving liquid which permits protracted preservation of blood. Further, this invention aims to provide a blood preserving liquid which can be used as a liquid preserver in the anticoagulant and the additive system.
From another aspect, the present invention has as one object thereof the provision of a plasticizer which exhibits no toxicity and possesses highly desirable compatibility and plasticizing efficiency relative to vinyl chloride type resins.
Another object of this invention is to provide vinyl chloride type resin compositions for medical appliances and medical implements which exhibit high physiological safety.
Still another object of this invention is to provide vinyl chloride type resin compositions for medical appliances and medical implements which possess thermal stability enough to withstand sterilization in an autoclave and high transparency, flexibility, and processibility.